Valsartan is indicated for the treatment of hypertension in adults and children six years and older, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which valsartan principally belongs. There are no controlled trials in hypertensive patients demonstrating risk reduction with valsartan.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Valsartan may be used alone or in combination with other antihypertensive agents.

Valsartan oral solution is indicated for the treatment of heart failure (NYHA class II-IV) to reduce the risk of hospitalization for heart failure in patients who are unable to swallow valsartan tablets. There is no evidence that valsartan provides added benefits when it is used with an adequate dose of an ACE inhibitor [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)and Clinical Studies (14.2)].

Valsartan oral solution is indicated to reduce the risk of cardiovascular death in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction who are unable to swallow valsartan tablets [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)and Clinical Studies (14.3)].

Valsartan oral solution is not therapeutically equivalent to the tablet formulation of Diovan. The peak concentration of valsartan with valsartan oral solution is higher than with Diovan [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]. Follow dosing instructions given here.

The recommended starting dose of valsartan oral solution is 40 mg or 80 mg twice daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions in blood pressure may be started at 80 mg administered twice a day. Valsartan oral solution may be used over a total daily dose range of 80 mg to 320 mg.

The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If additional antihypertensive effect is required over the starting dose range, the total daily dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg.

No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment, or for patients with mild or moderate liver insufficiency. Monitor closely patients with severe hepatic or renal impairment.

Valsartan oral solution may be administered with other antihypertensive agents.

The recommended starting dose is 0.65 mg/kg twice daily (up to 40 mg total daily dose). The dosage should be adjusted according to blood pressure response. Doses higher than 1.35 mg/kg twice daily (or >160 mg total daily dose) have not been studied in pediatric patients 6 to 16 years old.

No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m 2[see Use in Specific Populations (8.4)].

Valsartan oral solution is not recommended for patients under 6 years of age [see Adverse Reactions (6.1), Use  in Specific Populations (8.4), Clinical Studies (14.1)].

The recommended starting dose of valsartan oral solution is 40 mg twice daily. Titrate to 80 mg and 160 mg twice daily, as tolerated by the patient. Consider reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses.

Valsartan oral solution may be initiated as early as 12 hours after a myocardial infarction. The recommended starting dose of valsartan oral solution is 20 mg twice daily. Patients may be up titrated within 7 days to 40 mg twice daily, with subsequent titrations to a target maintenance dose of 160 mg twice daily, as tolerated by the patient. If symptomatic hypotension or renal dysfunction occurs, consider dosage reduction. Valsartan oral solution may be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin, beta-blockers, and statins.

4 mg/mL aqueous solution.

{ "type": "p", "children": [], "text": "4 mg/mL aqueous solution." }

Do not use in patients with known hypersensitivity to any component.

{ "type": "p", "children": [], "text": "Do not use in patients with known hypersensitivity to any component." }

Do not coadminister aliskiren with valsartan oral solution in patients with diabetes [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Do not coadminister aliskiren with valsartan oral solution in patients with diabetes\n \n [see\n \n Drug Interactions (7)].\n \n \n" }

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue valsartan oral solution as soon as possible [see Use in Specific Populations (8.1)].

In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision.

Peak plasma concentrations of valsartan are higher following administration of valsartan oral solution and may result in increased risk of hypotension as compared to administration of valsartan tablets [see Clinical Pharmacology (12.3)]. Patients with heart failure or post-myocardial infarction patients given valsartan tablets in clinical trials commonly had some reduction in blood pressure. Only use valsartan oral solution in heart failure or post-myocardial infarction patients who are unable to swallow valsartan tablets. In clinical trials of valsartan tablets, discontinuation of therapy because of continuing symptomatic hypotension usually was not necessary. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.

If symptomatic hypotension occurs, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin- angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan [see Drug Interactions (7)].

Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan oral solution may be required [see Adverse Reactions (6.1)].

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adult Hypertension

Valsartan has been evaluated for safety in more than 4,000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with valsartan was similar to placebo.

The overall frequency of adverse reactions was neither dose-related nor related to gender, age, race, or regimen. Discontinuation of therapy due to side effects was required in 2.3% of valsartan patients and 2.0% of placebo patients. The most common reasons for discontinuation of therapy with valsartan were headache and dizziness.

The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with valsartan and at a higher incidence in valsartan (n=2,316) than placebo (n=888) patients included fatigue (2% vs. 1%) and abdominal pain (2% vs. 1%).

Headache, dizziness, upper respiratory infection, cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and arthralgia occurred at a more than 1% rate, but at about the same incidence in placebo and valsartan patients.

In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE-inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p <0.001).

Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence of dizziness was observed in patients treated with valsartan 320 mg (8%) compared to 10 to 160 mg (2% to 4%).

Valsartan has been used concomitantly with hydrochlorothiazide without evidence of clinically important adverse interactions.

Other adverse reactions that occurred in controlled clinical trials of patients treated with valsartan (>0.2% of valsartan patients) are listed below. It cannot be determined whether these events were causally related to valsartan.

Body as a Whole:Allergic reaction and asthenia

Cardiovascular:Palpitations

Dermatologic:Pruritus and rash

Digestive:Constipation, dry mouth, dyspepsia, and flatulence

Musculoskeletal:Back pain, muscle cramps, and myalgia

Neurologic and Psychiatric:Anxiety, insomnia, paresthesia, and somnolence

Respiratory:Dyspnea

Special Senses:Vertigo

Urogenital:Impotence

Other reported events seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema.

Pediatric Hypertension

Valsartan has been evaluated for safety in over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years. No relevant differences were identified between the adverse experience profile for pediatric patients aged 6 to 16 years and that previously reported for adult patients. Headache and hyperkalemia were the most common adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively. Hyperkalemia was mainly observed in children with underlying renal disease.

Neurocognitive and developmental assessment of pediatric patients aged 6 to 16 years revealed no overall clinically relevant adverse impact after treatment with valsartan for up to 1 year.

Valsartan is not recommended for pediatric patients under 6 years of age. In a study (n=90) of pediatric patients (1 to 5 years), two deaths and three cases of on-treatment transaminase elevations were seen in the one-year open-label extension phase. These 5 events occurred in a study population in which patients frequently had significant co-morbidities. A causal relationship to valsartan has not been established. In a second study of 6-months duration in 75 children aged 1 to 5 years, there were no deaths; one case of marked liver transaminase elevations occurred following 6 months of treatment.

Heart Failure

The adverse experience profile of valsartan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the valsartan Heart Failure Trial, comparing valsartan in total daily doses up to 320 mg (n=2,506) to placebo (n=2,494), 10% of valsartan patients discontinued for adverse reactions vs. 7% of placebo patients.

The table shows adverse reactions in double-blind short-term heart failure trials, including the first 4 months of the valsartan Heart Failure Trial, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients. All patients received standard drug therapy for heart failure, frequently as multiple medications, which could include diuretics, digitalis, beta-blockers. About 93% of patients received concomitant ACE inhibitors.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" class="Noautorules" width="35%"> <tbody class="Headless"> <tr> <td valign="top"> <p class="First TableParagraph"></p> </td><td valign="top"> <p class="First TableParagraph"> <span class="Bold">Valsartan (n=3,282)</span> </p> </td><td valign="top"> <p class="First TableParagraph"> <span class="Bold">     Placebo (n=2,740)</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">Dizziness</p> </td><td valign="top"> <p class="First TableParagraph">     17%</p> </td><td valign="top"> <p class="First TableParagraph">       9%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">Hypotension</p> </td><td valign="top"> <p class="First TableParagraph">     7%</p> </td><td valign="top"> <p class="First TableParagraph">       2%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">Diarrhea</p> </td><td valign="top"> <p class="First TableParagraph">     5%</p> </td><td valign="top"> <p class="First TableParagraph">       4%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">Arthralgia</p> </td><td valign="top"> <p class="First TableParagraph">     3%</p> </td><td valign="top"> <p class="First TableParagraph">       2%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">Fatigue</p> </td><td valign="top"> <p class="First TableParagraph">     3%</p> </td><td valign="top"> <p class="First TableParagraph">       2%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">Back Pain</p> </td><td valign="top"> <p class="First TableParagraph">     3%</p> </td><td valign="top"> <p class="First TableParagraph">       2%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">Dizziness, postural</p> </td><td valign="top"> <p class="First TableParagraph">     2%</p> </td><td valign="top"> <p class="First TableParagraph">       1%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">Hyperkalemia</p> </td><td valign="top"> <p class="First TableParagraph">     2%</p> </td><td valign="top"> <p class="First TableParagraph">       1%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">Hypotension, postural</p> </td><td valign="top"> <p class="First TableParagraph">     2%</p> </td><td valign="top"> <p class="First TableParagraph">       1%</p> </td> </tr> </tbody> </table></div>

Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following: elevations in creatinine and elevations in potassium.

Other adverse reactions with an incidence greater than 1% and greater than placebo included headache, nausea, renal impairment, syncope, blurred vision, upper abdominal pain and vertigo.

From the long-term data in the valsartan Heart Failure Trial, there did not appear to be any significant adverse reactions not previously identified.

Post-Myocardial Infarction

The safety profile of valsartan was consistent with the pharmacology of the drug and the background diseases, cardiovascular risk factors, and clinical course of patients treated in the post-myocardial infarction setting. The table shows the percentage of patients discontinued in the valsartan and captopril-treated groups in the valsartan in Acute Myocardial Infarction Trial (VALIANT) with a rate of at least 0.5% in either of the treatment groups.

Discontinuations due to renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of  captopril-treated patients.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" class="Noautorules" width="35%"> <tbody class="Headless"> <tr> <td valign="top"> <p class="First TableParagraph"> <span class="Bold"></span> </p> </td><td valign="top"> <p class="First TableParagraph"> <span class="Bold">Valsartan (n=4,885)</span> <br/> <br/> </p> </td><td valign="top"> <p class="First TableParagraph"> <span class="Bold">   Captopril (n=4,879)</span> </p> </td> </tr> <tr> <td valign="top">Discontinuation for adverse <br/> reaction <br/> Adverse reactions </td><td valign="top"> <p class="First TableParagraph">5.8%</p> </td><td valign="top"> <p class="First TableParagraph">7.7%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">   Hypotension NOS</p> </td><td valign="top"> <p class="First TableParagraph">1.4%</p> </td><td valign="top"> <p class="First TableParagraph">   0.8%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">   Cough</p> </td><td valign="top"> <p class="First TableParagraph">0.6%</p> </td><td valign="top"> <p class="First TableParagraph">   2.5%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">   Blood creatinine increased</p> </td><td valign="top"> <p class="First TableParagraph">0.6%</p> </td><td valign="top"> <p class="First TableParagraph">   0.4%</p> </td> </tr> <tr> <td valign="top"> <p class="First TableParagraph">   Rash NOS</p> </td><td valign="top"> <p class="First TableParagraph">0.2%</p> </td><td valign="top"> <p class="First TableParagraph">   0.6%</p> </td> </tr> </tbody> </table></div>

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely  associated with administration of valsartan.

Creatinine:Minor elevations in creatinine occurred in 0.8% of patients taking valsartan and 0.6% given placebo in controlled clinical trials of hypertensive patients. In heart failure trials, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.

Hemoglobin and Hematocrit:Greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of valsartan patients, compared with 0.1% and 0.1% in placebo-treated patients.

Liver Function Tests:Occasional elevations (greater than 150%) of liver chemistries occurred in valsartan-treated patients. Three patients (<0.1%) treated with valsartan discontinued treatment for elevated liver chemistries.

Neutropenia:Neutropenia was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo.

Serum Potassium:In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of valsartan-treated patients compared to 2.9% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10.0% of valsartan- treated patients compared to 5.1% of placebo-treated patients.

Blood Urea Nitrogen (BUN):In heart failure trials, greater than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-treated patients.

The following additional adverse reactions have been reported in postmarketing experience:

Hypersensitivity:There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan should not be re-administered to patients who have had angioedema.

Digestive:Elevated liver enzymes and very rare reports of hepatitis

Renal:Impaired renal function, renal failure

Clinical Laboratory Tests:Hyperkalemia

Dermatologic:Alopecia, bullous dermatitis

Blood and Lymphatic:There are very rare reports of thrombocytopenia

Vascular:Vasculitis

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or establish a causal relationship to drug exposure.

Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium- sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co- medication is considered necessary, monitor serum potassium.

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including valsartan, may be attenuated by NSAIDs including  selective COX-2 inhibitors.

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on valsartan oral solution and other agents that affect the RAS.

Do not coadminister aliskiren with valsartan oral solution in patients with diabetes. Avoid use of aliskiren with valsartan oral solution in patients with renal impairment (GFR < 60 mL/min).

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including valsartan. Monitor serum lithium levels during concomitant use.

Risk Summary

Valsartan oral solution can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Published reports include cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan (see Clinical Considerations) . Studies in rats and rabbits with valsartan showed fetotoxicity only at maternally toxic doses (see Data) . When pregnancy is detected, discontinue valsartan oral solution as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal adverse reactions

Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

In patients taking valsartan oral solution during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in uteroexposure to valsartan oral solution for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of in uteroexposure to valsartan oral solution, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

Data

Animal Data

No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m 2basis. Calculations assume an oral dose of 320 mg/day and a 60-kg patient.

Risk Summary

There are no data on the presence of valsartan oral solution in human milk, the effects on the breastfed infant, or the effects on milk production. Valsartan is present in rat milk (see Data) . Because of the potential for valsartan to affect postnatal renal development in nursing infants, advise a nursing woman not to breastfeed during treatment with valsartan oral solution.

Data

Valsartan was detected in the milk of lactating rats 15 minutes after administration of a 3 mg/kg dose.

Valsartan is not recommended for pediatric patients under 6 years of age due to safety findings for which a relationship to treatment could not be excluded [see Adverse Reactions (6.1)] . Furthermore, it is unknown whether post-natal use of valsartan before maturation of renal function is complete has long-term deleterious effects on the kidney. In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age.

The antihypertensive effects of valsartan have been evaluated in two randomized, double-blind clinical studies in pediatric patients from 1-5 and 6-16 years of age [see Clinical Studies (14.1)] . The pharmacokinetics of valsartan have been evaluated in pediatric patients 1 to 16 years of age [see Clinical Pharmacology (12.3)]. Valsartan was generally well tolerated in children 6-16 years and the adverse experience profile was similar to that described for adults.

In children and adolescents with hypertension where underlying renal abnormalities may be more common, renal function and serum potassium should be closely monitored as clinically indicated.

No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m 2.

There is limited clinical experience with valsartan in pediatric patients with mild to moderate hepatic impairment [see Warnings and Precautions (5.3)] .

In the controlled clinical trials of valsartan, 1,214 (36.2%) hypertensive patients treated with valsartan were ≥65 years and 265 (7.9%) were ≥75 years. No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.

Of the 2,511 patients with heart failure randomized to valsartan in the valsartan Heart Failure Trial, 45% (1,141) were 65 years of age or older. In the valsartan in Acute Myocardial Infarction Trial (VALIANT), 53% (2,596) of the 4,909 patients treated with valsartan and 51% (2,515) of the 4,885 patients treated with valsartan + captopril were 65 years of age or older. There were no notable differences in efficacy or safety between older and younger patients in either trial.

Safety and effectiveness of valsartan in patients with severe renal impairment (CrCl ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.

No dose adjustment is necessary for patients with mild-to-moderate liver disease. No dosing recommendations can be provided for patients with severe liver disease.

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been reported. If symptomatic hypotension should occur, supportive treatment should be instituted.

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Valsartan is not removed from the plasma by hemodialysis.

{ "type": "p", "children": [], "text": "Valsartan is not removed from the plasma by hemodialysis." }

Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmosets, except for salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 31 times, respectively, the maximum recommended human dose on a mg/m 2basis). (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

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Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT 1receptor subtype.

{ "type": "p", "children": [], "text": "Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT\n \n 1receptor subtype.\n\n " }

Valsartan is chemically described as N-(1-oxopentyl)- N-[[2′-(1 H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine. Its empirical formula is C 24H 29N 5O 3, its molecular weight is 435.5, and its structural formula is:

{ "type": "p", "children": [], "text": "Valsartan is chemically described as\n \n N-(1-oxopentyl)-\n \n N-[[2′-(1\n \n H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine. Its empirical formula is C\n \n 24H\n \n 29N\n \n 5O\n \n 3, its molecular weight is 435.5, and its structural formula is:\n\n " }

Valsartan is an off white to white powder. It is soluble in methanol, freely soluble in anhydrous ethanol, sparingly soluble in methylene chloride, practically insoluble in water.

{ "type": "p", "children": [], "text": "Valsartan is an off white to white powder. It is soluble in methanol, freely soluble in anhydrous ethanol, sparingly soluble in methylene chloride, practically insoluble in water." }

Valsartan oral solution is formulated at a concentration of 4 mg/mL valsartan, as a clear, colorless solution with grape flavor, free from any visible foreign and particulate matter, free of precipitation and hazy mass. The inactive ingredients are: grape flavor, methylparaben, poloxamer, potassium sorbate, propylene glycol, sodium hydroxide, purified water, trisodium citrate dihydrate, and sucralose. Each 5 mL of Valsartan oral solution contains 18.46 mg of sodium.

{ "type": "p", "children": [], "text": "Valsartan oral solution is formulated at a concentration of 4 mg/mL valsartan, as a clear, colorless solution with grape flavor, free from any visible foreign and particulate matter, free of precipitation and hazy mass. The inactive ingredients are: grape flavor, methylparaben, poloxamer, potassium sorbate, propylene glycol, sodium hydroxide, purified water, trisodium citrate dihydrate, and sucralose. Each 5 mL of Valsartan oral solution contains 18.46 mg of sodium." }

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone- secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an AT 2receptor found in many tissues, but AT 2is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT 1receptor than for the AT 2receptor. The increased plasma levels of angiotensin II following AT 1receptor blockade with valsartan may stimulate the unblocked AT 2receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT 1receptor about one-200th that of valsartan itself.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.

Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available.

Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed.

In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.

In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.

For an equivalent dose, valsartan oral solution has 86% higher peak concentration (C max) and 25% higher area under the plasma concentration over time curve (AUC) for valsartan compared to Diovan. AUC and C maxof valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.

Absorption

Valsartan oral solution C maxis achieved 0.7 to 3.7 hours after dosing.

Effect of Food

High-fat, high-calorie meal decreased the AUC of valsartan oral solution by about 8% and C maxby about 44%.

Distribution

The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.

Elimination

Following intravenous administration, plasma clearance of valsartan is about 2 L/h. Renal clearance of valsartan is 0.62 L/h (about 30% of total body clearance). Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours.

Metabolism

The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitrometabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and co-administered drugs are unlikely because of the low extent of metabolism.

Excretion

When administered as an oral solution, 83% of the dose is recovered in feces and about 13% is recovered in urine. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.

Special Populations:

Geriatric Patients:Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young.

Pediatric Patients:In a study of pediatric hypertensive patients (n=26, 1 to 16 years of age) given single doses of a suspension of valsartan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was similar to that of adults receiving the same formulation.

Male and Female Patients:Pharmacokinetics of valsartan does not differ significantly between males and females.

Heart Failure Patients:The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to those observed in healthy volunteers. AUC and C maxvalues of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients.

Patients with Renal Impairment:There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, monitor closely [see Dosage and Administration (2.1)].

Patients with Hepatic Impairment:On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex, and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Monitor closely patients with liver disease [see Dosage and Administration (2.1)].

Drug Interactions

No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with nebivolol, amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin.

Co-administration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time- course of the anticoagulant properties of warfarin.

Transporters:The results from an in vitrostudy with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose on a mg/m 2basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella(Ames) and E. coli;a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m 2basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10% of the maximum recommended pediatric dose on a mg/m 2basis) from postnatal day 7 to postnatal day 70 produced persistent, irreversible kidney damage. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life.

Studies evaluating the antihypertensive effects of valsartan were conducted with a formulation that is not therapeutically equivalent to valsartan oral solution [see Clinical Pharmacology (12.3)] .

Adult Hypertension

The antihypertensive effects of valsartan were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (1 in patients over 65 years) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95-115 mmHg. The studies allowed comparison of once-daily and twice- daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.

Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of valsartan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear.

Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.

The blood pressure-lowering effect of valsartan and thiazide-type diuretics are approximately additive.

The 7 studies of valsartan monotherapy included over 2,000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80 to 160 mg and 9/6 mmHg at 320 mg. In a controlled trial the addition of HCTZ to valsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone.

Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups.

In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg.

There are no trials of valsartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

There was essentially no change in heart rate in valsartan-treated patients in controlled trials.

Pediatric Hypertension

The antihypertensive effects of valsartan were evaluated in two randomized, double-blind clinical  studies.

In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses).

Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study. At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by -8, -10, -12 mmHg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was -4 and -7 mmHg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.

In a clinical study involving 90 hypertensive pediatric patients 1 to 5 years of age with a similar study design, there was some evidence of effectiveness, but safety findings for which a relationship to treatment could not be excluded mitigate against recommending use in this age group [see Adverse Reactions (6.1)].

The valsartan Heart Failure Trial (Val-HeFT) was a multinational, double-blind study in which 5,010 patients with NYHA class II (62%) to IV (2%) heart failure and LVEF <40%, on baseline therapy chosen by their physicians, were randomized to placebo or valsartan (titrated from 40 mg twice daily to the highest tolerated dose or 160 mg twice daily) and followed for a mean of about 2 years. The VAL-HeFT study was conducted with a formulation of valsartan that is not therapeutically equivalent to valsartan oral solution [see Clinical Pharmacology (12.3)] . Although Val-HeFT’s primary goal was to examine the effect of valsartan when added to an ACE inhibitor, about 7% were not receiving an ACE inhibitor. Other background therapy included diuretics (86%), digoxin (67%), and beta-blockers (36%). The population studied was 80% male, 46% 65 years or older and 89% Caucasian. At the end of the trial, patients in the valsartan group had a blood pressure that was 4 mmHg systolic and 2 mmHg diastolic lower than the placebo group. There were two primary end points, both assessed as time to first event: all-cause mortality and heart failure morbidity, the latter defined as all-cause mortality, sudden death with resuscitation, hospitalization for heart failure, and the need for intravenous inotropic or vasodilatory drugs for at least 4 hours. These results are summarized in the following table.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" width="50%"> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"></td><td class="Toprule" valign="top"> <p class="First First TableParagraph"> <span class="Bold">    Placebo</span> </p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph"> <span class="Bold">    Valsartan</span> </p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph"> <span class="Bold">    Hazard Ratio</span> </p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph"> <span class="Bold">    Nominal</span> </p> </td> </tr> <tr> <td valign="top"></td><td valign="top"> <p class="First First TableParagraph">    (N=2,499)</p> </td><td valign="top"> <p class="First First TableParagraph">    (N=2,511)</p> </td><td valign="top"> <p class="First First TableParagraph">    (95% CI*)</p> </td><td valign="top"> <p class="First First TableParagraph">    p-value</p> </td> </tr> <tr> <td valign="top"> <p class="First">All-cause</p> <p class="TableParagraph">mortality</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    484</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    495</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    1.02</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    0.8</p> </td> </tr> <tr> <td valign="top"></td><td valign="top"> <p class="First First TableParagraph">    (19.4%)</p> </td><td valign="top"> <p class="First First TableParagraph">    (19.7%)</p> </td><td valign="top"> <p class="First First TableParagraph">    (0.90-1.15)</p> </td><td valign="top"></td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph">HF morbidity</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    801</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    723</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    0.87</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    0.009</p> </td> </tr> <tr> <td valign="top"></td><td valign="top"> <p class="First First TableParagraph">    (32.1%)</p> </td><td valign="top"> <p class="First First TableParagraph">    (28.8%)</p> </td><td valign="top"> <p class="First First TableParagraph">    (0.79-0.97)</p> </td><td valign="top"></td> </tr> <tr class="Last"> <td class="Toprule" colspan="3" valign="top"> <p class="First First TableParagraph">* CI = Confidence Interval</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> </tbody> </table></div>

Although the overall morbidity result favored valsartan, this result was largely driven by the 7% of patients not receiving an ACE inhibitor, as shown in the following table.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" width="50%"> <tbody class="Headless"> <tr class="First"> <td rowspan="2" valign="top"></td><td class="BotRule" valign="top"> <p class="First First TableParagraph"> <span class="Bold">Without ACE Inhibitor</span> </p> </td><td valign="top"> <p class="First First TableParagraph"> <span class="Bold">    With ACE Inhibitor</span> </p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph"> <span class="Bold">Placebo               Valsartan</span> </p> <p class="TableParagraph">(N=181)               (N=185)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph"> <span class="Bold">    Placebo                   Valsartan</span> </p> <p class="TableParagraph">    (N=2,318)               (N=2,326)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph">Events (%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">77 (42.5%)           46 (24.9%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    724 (31.2%)            677 (29.1%)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph">Hazard ratio (95% CI)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">0.51 (0.35, 0.73)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">0.92 (0.82, 1.02)</p> </td> </tr> <tr class="Last"> <td class="Toprule" valign="top"> <p class="First First TableParagraph">p-value</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">0.0002</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">0.0965</p> </td> </tr> </tbody> </table></div>

The modest favorable trend in the group receiving an ACE inhibitor was largely driven by the patients receiving less than the recommended dose of ACE inhibitor. Thus, there is little evidence of further clinical benefit when valsartan is added to an adequate dose of ACE inhibitor.

Secondary end points in the subgroup not receiving ACE inhibitors were as follows.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" width="50%"> <tbody class="Headless"> <tr class="First"> <td rowspan="2" valign="top"></td><td valign="top"> <p class="First First TableParagraph"> <span class="Bold">  Placebo</span> </p> </td><td valign="top"> <p class="First First TableParagraph"> <span class="Bold">    Valsartan</span> </p> </td><td valign="top"> <p class="First First TableParagraph"> <span class="Bold">    Hazard Ratio</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First First TableParagraph"> <span class="Bold">  (N=181)</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">    (N=185)</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">    (95% CI)</span> </p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph">Components of HF morbidity</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph">All-cause mortality</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    49 (27.1%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    32 (17.3%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    0.59 (0.37, 0.91)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph">Sudden death with resuscitation</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    2 (1.1%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    1 (0.5%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    0.47 (0.04, 5.20)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph">CHF therapy</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    1 (0.6%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    0 (0.0%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    –</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph">CHF hospitalization</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    48 (26.5%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    24 (13.0%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    0.43 (0.27, 0.71)</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First First TableParagraph">Cardiovascular mortality</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    40 (22.1%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    29 (15.7%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    0.65 (0.40, 1.05)</p> </td> </tr> <tr class="Last"> <td class="Toprule" valign="top"> <p class="First First TableParagraph">Non-fatal morbidity</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    49 (27.1%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    24 (13.0%)</p> </td><td class="Toprule" valign="top"> <p class="First First TableParagraph">    0.42 (0.26, 0.69)</p> </td> </tr> </tbody> </table></div>

In patients not receiving an ACE inhibitor, valsartan-treated patients had an increase in ejection fraction and reduction in left ventricular internal diastolic diameter (LVIDD).

Effects were generally consistent across subgroups defined by age and gender for the population of patients not receiving an ACE inhibitor. The number of black patients was small and does not permit a meaningful assessment in this subset of patients.

The VALsartan In Acute myocardial iNfarcTion trial (VALIANT) was a randomized, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and either heart failure (signs, symptoms or radiological evidence) or left ventricular systolic dysfunction (ejection fraction ≤40% by radionuclide ventriculography or ≤35% by echocardiography or ventricular contrast angiography). The VALIANT study was conducted with a formulation of valsartan that is not therapeutically equivalent to valsartan oral solution [see Clinical Pharmacology (12.3)] . Patients were randomized within 12 hours to 10 days after the onset of myocardial infarction symptoms to one of three treatment groups: valsartan (titrated from 20 or 40 mg twice daily to the highest tolerated dose up to a maximum of 160 mg twice daily), the ACE inhibitor, captopril (titrated from 6.25 mg three times daily to the highest tolerated dose up to a maximum of 50 mg three times daily), or the combination of valsartan plus captopril. In the combination group, the dose of valsartan was titrated from 20 mg twice daily to the highest tolerated dose up to a maximum of 80 mg twice daily; the dose of captopril was the same as for monotherapy. The population studied was 69% male, 94% Caucasian, and 53% were 65 years of age or older. Baseline therapy included aspirin (91%), beta-blockers (70%), ACE inhibitors (40%), thrombolytics (35%) and statins (34%). The mean treatment duration was 2 years. The mean daily dose of valsartan in the monotherapy group was 217 mg.

The primary endpoint was time to all-cause mortality. Secondary endpoints included (1) time to cardiovascular (CV) mortality, and (2) time to the first event of cardiovascular mortality, reinfarction, or hospitalization for heart failure. The results are summarized in the following table.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="50%"> <tbody class="Headless"> <tr class="First"> <td rowspan="2" valign="top"></td><td colspan="2" valign="top"> <p class="First"> <span class="Bold">Valsartan vs. Captopril</span> </p> <p> <span class="Bold">(N=4,909) (N=4,909)</span> </p> </td><td valign="top"></td><td colspan="3" valign="top"> <p class="First"> <span class="Bold">Valsartan + Captopril vs. Captopril</span> </p> <p> <span class="Bold">               (N=4,885)  (N=4,909)</span> </p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">No. of Deaths <br/> Valsartan/Captopril </span> </p> </td><td class="Toprule" valign="top"> <p class="First"> <span class="Bold">   Hazard <br/>    Ratio <br/>    CI </span> </p> </td><td class="Toprule" valign="top"> <p class="First"> <span class="Bold">   p-value</span> </p> </td><td class="Toprule" valign="top"> <p class="First"> <span class="Bold">   No. of Deaths <br/> Comb/Captopril </span> </p> </td><td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Hazard <br/> Ratio <br/> CI </span> </p> </td><td class="Toprule" valign="top"> <p class="First"> <span class="Bold">p-value</span> </p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">All-cause <br/> mortality </p> <p></p> </td><td class="Toprule" valign="top"> <p class="First">   979 (19.9%)</p> <p>   /958 (19.5%)</p> </td><td class="Toprule" valign="top"> <p class="First">1.001</p> <p>(0.902,</p> <p>1.111)</p> </td><td class="Toprule" valign="top"> <p class="First">    0.98</p> <p></p> </td><td class="Toprule" valign="top"> <p class="First">941 (19.3%)</p> <p>/958 (19.5%)</p> <p></p> </td><td class="Toprule" valign="top"> <p class="First">0.984</p> <p>(0.886,</p> <p>1.093)</p> <p></p> </td><td class="Toprule" valign="top"> <p class="First">0.73</p> <p></p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">CV mortality</p> </td><td class="Toprule" valign="top"> <p class="First">   827 (16.8%)</p> <p>   /830 (16.9%)</p> </td><td class="Toprule" valign="top"> <p class="First">0.976</p> <p>(0.875,</p> <p>   1.090)</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr class="Last"> <td class="Toprule" valign="top"> <p class="First">CV mortality,</p> <p>hospitalization</p> <p>for HF, and</p> <p>recurrent non-</p> <p>fatal MI</p> </td><td class="Toprule" valign="top"> <p class="First">   1,529 (31.1%)</p> <p>   /1,567 (31.9%)</p> </td><td class="Toprule" valign="top"> <p class="First">0.955</p> <p>(0.881,</p> <p>1.035)</p> <p></p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> </tbody> </table></div>

There was no difference in overall mortality among the three treatment groups. There was thus no evidence that combining the ACE inhibitor captopril and the angiotensin II blocker valsartan was of value.

The data were assessed to see whether the effectiveness of valsartan could be demonstrated by showing in a non-inferiority analysis that it preserved a fraction of the effect of captopril, a drug with a demonstrated survival effect in this setting. A conservative estimate of the effect of captopril (based on a pooled analysis of 3 post-infarction studies of captopril and 2 other ACE inhibitors) was a 14% to 16% reduction in mortality compared to placebo. Valsartan would be considered effective if it preserved a meaningful fraction of that effect and unequivocally preserved some of that effect. As shown in the table, the upper bound of the CI for the hazard ratio (valsartan/captopril) for overall or CV mortality is 1.09 to 1.11, a difference of about 9% to 11%, thus making it unlikely that valsartan has less than about half of the estimated effect of captopril and clearly demonstrating an effect of valsartan. The other secondary endpoints were consistent with this conclusion.

Effects on Mortality Amongst Subgroups in VALIANT

There were no clear differences in all-cause mortality based on age, gender, race, or baseline therapies, as shown in the figure above.

Valsartan Oral Solution containing 4 mg/mL valsartan, USP for oral administration. Each mL contains 4 mg valsartan. It is a clear, colorless solution and is supplied as:

{ "type": "p", "children": [], "text": "Valsartan Oral Solution containing 4 mg/mL valsartan, USP for oral administration. Each mL contains 4 mg valsartan. It is a clear, colorless solution and is supplied as:" }

White HDPE bottles of 120 mL: NDC 72888-184-48

{ "type": "p", "children": [], "text": "White HDPE bottles of 120 mL: NDC 72888-184-48" }

White HDPE bottles of 473 mL: NDC 72888-184-13

{ "type": "p", "children": [], "text": "White HDPE bottles of 473 mL: NDC 72888-184-13" }

Store at 20 °C-25 °C (68 °F-77 °F); excursions permitted to 15 °C -30 °C (59 °F -86 °F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20 °C-25 °C (68 °F-77 °F); excursions permitted to 15 °C -30 °C (59 °F -86 °F) [see USP Controlled Room Temperature]." }

Dispense in tight container (USP).

{ "type": "p", "children": [], "text": "Dispense in tight container (USP)." }

Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.1)and Use in Specific Populations (8.1)] .

{ "type": "p", "children": [], "text": "\nFetal Toxicity\n Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider with a known or suspected pregnancy\n \n [see\n \n Warnings and Precautions (5.1)and\n \n Use in Specific Populations (8.1)]\n \n .\n\n " }

Lactation Advise women not to breastfeed during treatment with valsartan oral solution [see Use in Specific Populations (8.2)] .

{ "type": "p", "children": [], "text": "\nLactation\n Advise women not to breastfeed during treatment with valsartan oral solution\n \n [see\n \n Use in Specific Populations (8.2)]\n \n .\n\n " }

Symptomatic Hypotension Advise patients that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell patients that if syncope occurs to discontinue valsartan oral solution until the physician has been consulted. Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

{ "type": "p", "children": [], "text": "\nSymptomatic Hypotension\n Advise patients that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell patients that if syncope occurs to discontinue valsartan oral solution until the physician has been consulted. \n Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.\n\n " }

Hyperkalemia Advise patients not to use salt substitutes containing potassium without consulting their physician.

{ "type": "p", "children": [], "text": "\nHyperkalemia\n Advise patients not to use salt substitutes containing potassium without consulting their physician.\n\n " }

All trademarks are the property of their respective owners.

{ "type": "p", "children": [], "text": "All trademarks are the property of their respective owners." }

Distributed by: Advagen Pharma Ltd., East Windsor, NJ 08520, USA.

{ "type": "p", "children": [], "text": "\nDistributed by:\n Advagen Pharma Ltd., \n East Windsor, NJ 08520, USA.\n\n " }

Manufactured by: Rubicon Research Limited Satara 415004, India.

{ "type": "p", "children": [], "text": "\nManufactured by:\n Rubicon Research Limited \n Satara 415004, India.\n\n " }

Revised: 05/2025

{ "type": "p", "children": [], "text": "Revised: 05/2025" }

Valsartan Oral Solution 20 mg/5mL (4 mg/mL) NDC-72888-184-13 - 473mL - Bottle label

{ "type": "p", "children": [], "text": "\nValsartan Oral Solution 20 mg/5mL (4 mg/mL) NDC-72888-184-13 - 473mL - Bottle label\n" }

Valsartan Oral Solution 20 mg/5mL (4 mg/mL) NDC-72888-184-48 - 120mL - Bottle label

{ "type": "p", "children": [], "text": "\nValsartan Oral Solution 20 mg/5mL (4 mg/mL) NDC-72888-184-48 - 120mL - Bottle label\n" }

Amlodipine/valsartan/hydrochlorothiazide is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including amlodipine, hydrochlorothiazide, and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with amlodipine/valsartan/hydrochlorothiazide.

{ "type": "p", "children": [], "text": "\nAmlodipine/valsartan/hydrochlorothiazide is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including amlodipine, hydrochlorothiazide, and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with amlodipine/valsartan/hydrochlorothiazide." }

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

{ "type": "p", "children": [], "text": "Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC)." }

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

{ "type": "p", "children": [], "text": "Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly." }

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

{ "type": "p", "children": [], "text": "Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal." }

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

{ "type": "p", "children": [], "text": "Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy." }

Limitation of Use

{ "type": "p", "children": [], "text": "\nLimitation of Use\n" }

Amlodipine/valsartan/hydrochlorothiazide is not indicated for the initial therapy of hypertension [see Dosage and Administration (2)].

{ "type": "p", "children": [], "text": "Amlodipine/valsartan/hydrochlorothiazide is not indicated for the initial therapy of hypertension\n \n [see Dosage and Administration (2)].\n" }

Dose once-daily. The dosage may be increased after 2 weeks of therapy. The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose of amlodipine/valsartan/hydrochlorothiazide. The maximum recommended dose of amlodipine/valsartan/hydrochlorothiazide is 10/320/25 mg.

Amlodipine/valsartan/hydrochlorothiazide may be used for patients not adequately controlled on any 2 of the following antihypertensive classes: calcium channel blockers, angiotensin receptor blockers, and diuretics.

A patient who experiences dose-limiting adverse reactions to an individual component while on any dual combination of the components of amlodipine/valsartan/hydrochlorothiazide may be switched to amlodipine/valsartan/hydrochlorothiazide containing a lower dose of that component to achieve similar blood pressure reductions.

Amlodipine/valsartan/hydrochlorothiazide may be substituted for the individually titrated components.

Amlodipine/valsartan/hydrochlorothiazide may be administered with other antihypertensive agents.

Amlodipine/valsartan/hydrochlorothiazide tablets are available as follows:

{ "type": "p", "children": [], "text": "\nAmlodipine/valsartan/hydrochlorothiazide tablets are available as follows:" }

{ "type": "ul", "children": [ "5 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets – White to off-white, film coated, oval shaped biconvex tablets, debossed with \"P\" on one side of the tablet and \"172\" on the other.", "10 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets – Peach to light brown, film coated, oval shaped biconvex tablets, debossed with \"P\" on one side of the tablet and \"174\" on the other.", "5 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets – Yellow, film-coated, oval shaped biconvex tablets debossed with \"P\" on one side of the tablet and \"173\" on the other.", "10 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets – Bright yellow, film-coated, oval shaped, biconvex tablets debossed with \"P\" on one side of the tablet and \"185\" on the other.", "10 mg amlodipine /320 mg valsartan /25 mg hydrochlorothiazide Tablets – White to off-white, film coated, oval shaped biconvex tablets, debossed with \"P\" on one side of the tablet and \"175\" on the other." ], "text": "" }

Do not use in patients with anuria, hypersensitivity to other sulfonamide-derived drugs, or hypersensitivity to any component of this product.

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Do not coadminister aliskiren with amlodipine/valsartan/hydrochlorothiazide in patients with diabetes [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Do not coadminister aliskiren with amlodipine/valsartan/hydrochlorothiazide in patients with diabetes\n \n [see Drug Interactions (7)].\n" }

Valsartan

Amlodipine/valsartan/hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Amlodipine/valsartan/hydrochlorothiazide as soon as possible [see Use in Specific Populations (8.1)].

Hydrochlorothiazide

Thiazides cross the placenta, and use of thiazides during pregnancy is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with the maximum dose of amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg) compared to 1.8% of valsartan/HCTZ (320/25 mg) patients, 0.4% of amlodipine/valsartan (10/320 mg) patients, and 0.2% of HCTZ/amlodipine (25/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension. In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Correct this condition prior to administration of amlodipine/valsartan/hydrochlorothiazide.

Amlodipine/valsartan/hydrochlorothiazide has not been studied in patients with heart failure, recent myocardial infarction, or in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.

Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Do not initiate treatment with amlodipine/valsartan/hydrochlorothiazide in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

If excessive hypotension occurs with amlodipine/valsartan/hydrochlorothiazide, place the patient in a supine position and, if necessary, give intravenous normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

Changes in renal function, including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on amlodipine/valsartan/hydrochlorothiazide. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on amlodipine/valsartan/hydrochlorothiazide [see Drug Interactions (7)].

In the controlled trial of amlodipine/valsartan/hydrochlorothiazide in moderate to severe hypertensive patients, the incidence of hypokalemia (serum potassium <3.5 mEq/L) at any time post-baseline with the maximum dose of amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg) was 10% compared to 25% with HCTZ/amlodipine (25/10 mg), 7% with valsartan/HCTZ (320/25 mg), and 3% with amlodipine/valsartan (10/320 mg). One patient (0.2%) discontinued therapy due to an adverse event of hypokalemia in each of the amlodipine/valsartan/hydrochlorothiazide and HCTZ/amlodipine groups. The incidence of hyperkalemia (serum potassium > 5.7 mEq/L) was 0.4% with amlodipine/valsartan/hydrochlorothiazide compared to 0.2% to 0.7% with the dual therapies.

Some patients with heart failure have developed increases in potassium on valsartan. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required.

Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.

If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), amlodipine/valsartan/hydrochlorothiazide should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.  

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of valsartan or thiazide diuretics. Monitor lithium levels in patients receiving amlodipine,valsartan and hydrochlorothiazide and lithium [see Drug Interactions (7)].

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving amlodipine/valsartan/hydrochlorothiazide.

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

In the controlled trial of amlodipine/valsartan/hydrochlorothiazide, where only the maximum dose (10/320/25 mg) was evaluated, safety data were obtained in 582 patients with hypertension. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.

The overall frequency of adverse reactions was similar between men and women, younger (< 65 years) and older (≥ 65 years) patients, and black and white patients. In the active controlled clinical trial, discontinuation because of adverse events occurred in 4.0% of patients treated with amlodipine/valsartan/hydrochlorothiazide 10/320/25 mg compared to 2.9% of patients treated with valsartan/HCTZ 320/25 mg, 1.6% of patients treated with amlodipine/valsartan 10/320 mg, and 3.4% of patients treated with HCTZ/amlodipine 25/10 mg.  The most common reasons for discontinuation of therapy with amlodipine/valsartan/hydrochlorothiazide were dizziness (1.0%) and hypotension (0.7%).

The most frequent adverse events that occurred in the active controlled clinical trial in at least 2% of patients treated with amlodipine/valsartan/hydrochlorothiazide are presented in the following table.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"></td><td align="center" class="Botrule Rrule Toprule"><span class="Bold">Aml/Val/HCTZ</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold">Val/HCTZ</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold">Aml/Val</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold">HCTZ/Aml</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="bottom"><span class="Bold">Preferred Term</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold">10/320/25 mg</span> <br/> <span class="Bold">N=582</span> <br/> <span class="Bold">n (%)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold">320/25 mg</span> <br/> <span class="Bold">N=559</span> <br/> <span class="Bold">n (%)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold">10/320 mg</span> <br/> <span class="Bold">N=566</span> <br/> <span class="Bold">n (%)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold">25/10 mg</span> <br/> <span class="Bold">N=561</span> <br/> <span class="Bold">n (%)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  <span class="Bold">Dizziness</span> <br/> </td><td align="center" class="Botrule Rrule">48 ( 8.2) <br/> </td><td align="center" class="Botrule Rrule">40 ( 7.2) <br/> </td><td align="center" class="Botrule Rrule">14 ( 2.5) <br/> </td><td align="center" class="Botrule Rrule">23 ( 4.1) <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  <span class="Bold">Edema</span> <br/> </td><td align="center" class="Botrule Rrule">38 ( 6.5) <br/> </td><td align="center" class="Botrule Rrule">8 ( 1.4) <br/> </td><td align="center" class="Botrule Rrule">65 (11.5) <br/> </td><td align="center" class="Botrule Rrule">63 ( 11.2) <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  <span class="Bold">Headache</span> <br/> </td><td align="center" class="Botrule Rrule">30 (5.2) <br/> </td><td align="center" class="Botrule Rrule">31 (5.5) <br/> </td><td align="center" class="Botrule Rrule">30 (5.3) <br/> </td><td align="center" class="Botrule Rrule">40 (7.1) <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  <span class="Bold">Dyspepsia</span> <br/> </td><td align="center" class="Botrule Rrule">13 ( 2.2) <br/> </td><td align="center" class="Botrule Rrule">5 ( 0.9) <br/> </td><td align="center" class="Botrule Rrule">6 ( 1.1) <br/> </td><td align="center" class="Botrule Rrule">2 ( 0.4) <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  <span class="Bold">Fatigue</span> <br/> </td><td align="center" class="Botrule Rrule">13 ( 2.2) <br/> </td><td align="center" class="Botrule Rrule">15 ( 2.7) <br/> </td><td align="center" class="Botrule Rrule">12 ( 2.1) <br/> </td><td align="center" class="Botrule Rrule">8 ( 1.4) <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  <span class="Bold">Muscle spasms</span> <br/> </td><td align="center" class="Botrule Rrule">13 ( 2.2) <br/> </td><td align="center" class="Botrule Rrule">7 ( 1.3) <br/> </td><td align="center" class="Botrule Rrule">7 ( 1.2) <br/> </td><td align="center" class="Botrule Rrule">5 ( 0.9) <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  <span class="Bold">Back pain</span> <br/> </td><td align="center" class="Botrule Rrule">12 ( 2.1) <br/> </td><td align="center" class="Botrule Rrule">13 ( 2.3) <br/> </td><td align="center" class="Botrule Rrule">5 ( 0.9) <br/> </td><td align="center" class="Botrule Rrule">12 ( 2.1) <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  <span class="Bold">Nausea</span> <br/> </td><td align="center" class="Botrule Rrule">12 ( 2.1) <br/> </td><td align="center" class="Botrule Rrule">7 ( 1.3) <br/> </td><td align="center" class="Botrule Rrule">10 ( 1.8) <br/> </td><td align="center" class="Botrule Rrule">12 ( 2.1) <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">  <span class="Bold">Nasopharyngitis</span> <br/> </td><td align="center" class="Botrule Rrule">12 (2.1) <br/> </td><td align="center" class="Botrule Rrule">13 (2.3) <br/> </td><td align="center" class="Botrule Rrule">13 (2.3) <br/> </td><td align="center" class="Botrule Rrule">12 (2.1) <br/> </td> </tr> </tbody> </table></div>

Orthostatic events (orthostatic hypotension and postural dizziness) were seen in 0.5% of patients.

Valsartan

Valsartan has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p < 0.001).

Clinical Laboratory Test Findings

Clinical laboratory test findings for amlodipine/valsartan/hydrochlorothiazide were obtained in a controlled trial of amlodipine/valsartan/hydrochlorothiazide administered at the maximal dose of 10/320/25 mg compared to maximal doses of dual therapies, i.e., valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, and HCTZ/amlodipine 25/10 mg. Findings for the components of amlodipine/valsartan/hydrochlorothiazide were obtained from other trials.

Creatinine:In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.

Blood Urea Nitrogen (BUN):In hypertensive patients, greater than 50% increases in BUN were observed in 30% of amlodipine/valsartan/hydrochlorothiazide-treated patients compared to 29% of valsartan/HCTZ patients, 15.8% of amlodipine/valsartan patients, and 18.5% of HCTZ/amlodipine patients. In heart failure patients, greater than 50% increases in BUN were observed in 17% of valsartan-treated patients compared to 6% of placebo-treated patients [see Warnings and Precautions (5.4)].

Neutropenia:Neutropenia (< 1500/L) was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo.

The following additional adverse reactions have been reported in postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Amlodipine

With amlodipine, gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

Valsartan

The following additional adverse reactions have been reported in postmarketing experience with valsartan or valsartan/hydrochlorothiazide:

Blood and Lymphatic:Decrease in hemoglobin, decrease in hematocrit, neutropenia

Hypersensitivity:Angioedema has been reported. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Amlodipine/valsartan/hydrochlorothiazide should not be re-administered to patients who have had angioedema.

Digestive:Elevated liver enzymes and reports of hepatitis

Musculoskeletal:Rhabdomyolysis

Renal:Impaired renal function, renal failure

Dermatologic:Alopecia, bullous dermatitis

Vascular:Vasculitis

Nervous System:Syncope

Hydrochlorothiazide

The following additional adverse reactions have been reported in postmarketing experience with hydrochlorothiazide:

Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, visual impairment.

Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary.

Non-melanoma Skin Cancer:Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥ 50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

No drug interaction studies have been conducted with amlodipine/valsartan/hydrochlorothiazide and other drugs, although studies have been conducted with the individual components. A pharmacokinetic drug-drug interaction study has been conducted to address the potential for pharmacokinetic interaction between the triple combination, amlodipine/valsartan/hydrochlorothiazide, and the corresponding 3 double combinations. No clinically relevant interaction was observed.

{ "type": "p", "children": [], "text": "\nNo drug interaction studies have been conducted with amlodipine/valsartan/hydrochlorothiazide and other drugs, although studies have been conducted with the individual components. A pharmacokinetic drug-drug interaction study has been conducted to address the potential for pharmacokinetic interaction between the triple combination, amlodipine/valsartan/hydrochlorothiazide, and the corresponding 3 double combinations. No clinically relevant interaction was observed." }

Amlodipine

{ "type": "p", "children": [], "text": "\nAmlodipine\n" }

Impact of Other Drugs on Amlodipine

{ "type": "p", "children": [], "text": "\nImpact of Other Drugs on Amlodipine\n" }

CYP3A Inhibitors

{ "type": "p", "children": [], "text": "\nCYP3A Inhibitors\n" }

Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A inhibitors to determine the need for dose adjustment\n \n [see Clinical Pharmacology (12.3)].\n" }

CYP3A Inducers

{ "type": "p", "children": [], "text": "\nCYP3A Inducers\n" }

No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is coadministered with CYP3A inducers (e.g., rifampicin, St. John's Wort).

{ "type": "p", "children": [], "text": "No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is coadministered with CYP3A inducers (e.g., rifampicin, St. John's Wort)." }

Sildenafil

{ "type": "p", "children": [], "text": "\nSildenafil\n" }

Monitor for hypotension when sildenafil is coadministered with amlodipine [see Clinical Pharmacology (12.2)].

{ "type": "p", "children": [], "text": "Monitor for hypotension when sildenafil is coadministered with amlodipine\n \n [see Clinical Pharmacology (12.2)].\n" }

Impact of Amlodipine on Other Drugs

{ "type": "p", "children": [], "text": "\nImpact of Amlodipine on Other Drugs\n" }

Simvastatin

{ "type": "p", "children": [], "text": "\nSimvastatin\n" }

Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily\n \n [see Clinical Pharmacology (12.3)].\n" }

Immunosuppressants

{ "type": "p", "children": [], "text": "\nImmunosuppressants\n" }

Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when coadministered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when coadministered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate\n \n [see Clinical Pharmacology (12.3)].\n" }

Valsartan

{ "type": "p", "children": [], "text": "\nValsartan\n" }

Agents Increasing Serum Potassium:Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable.

{ "type": "p", "children": [], "text": "\nAgents Increasing Serum Potassium:Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable.\n\n " }

Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors):In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy.

{ "type": "p", "children": [], "text": "\nNon-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors):In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy.\n\n " }

The antihypertensive effect of angiotensin II receptor antagonists, including valsartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

{ "type": "p", "children": [], "text": "The antihypertensive effect of angiotensin II receptor antagonists, including valsartan, may be attenuated by NSAIDs including selective COX-2 inhibitors." }

Dual Blockade of the Renin-Angiotensin System (RAS):Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on valsartan and other agents that affect the RAS.

{ "type": "p", "children": [], "text": "\nDual Blockade of the Renin-Angiotensin System (RAS):Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on valsartan and other agents that affect the RAS.\n\n " }

Do not coadminister aliskiren with valsartan in patients with diabetes. Avoid use of aliskiren with valsartan in patients with renal impairment (GFR < 60 mL/min).

{ "type": "p", "children": [], "text": "Do not coadminister aliskiren with valsartan in patients with diabetes. Avoid use of aliskiren with valsartan in patients with renal impairment (GFR < 60 mL/min)." }

Valsartan – Hydrochlorothiazide

{ "type": "p", "children": [], "text": "\nValsartan – Hydrochlorothiazide\n" }

Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or thiazides. Monitor lithium levels in patients taking amlodipine, valsartan and hydrochlorothiazide.

{ "type": "p", "children": [], "text": "\nLithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or thiazides. Monitor lithium levels in patients taking amlodipine, valsartan and hydrochlorothiazide.\n\n " }

Hydrochlorothiazide

{ "type": "p", "children": [], "text": "\nHydrochlorothiazide\n" }

When administered concurrently the following drugs may interact with thiazide diuretics:

{ "type": "p", "children": [], "text": "When administered concurrently the following drugs may interact with thiazide diuretics:" }

Antidiabetic Drugs (oral agents and insulin):Dosage adjustment of the antidiabetic drug may be required.

{ "type": "p", "children": [], "text": "\nAntidiabetic Drugs (oral agents and insulin):Dosage adjustment of the antidiabetic drug may be required.\n\n " }

Non-Steroidal Anti-inflammatory Drugs(NSAIDs and COX-2 selective inhibitors): When amlodipine/valsartan/hydrochlorothiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of diuretic is obtained.

{ "type": "p", "children": [], "text": "\nNon-Steroidal Anti-inflammatory Drugs(NSAIDs and COX-2 selective inhibitors): When amlodipine/valsartan/hydrochlorothiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of diuretic is obtained.\n\n " }

Carbamazepine:May lead to symptomatic hyponatremia.

{ "type": "p", "children": [], "text": "\nCarbamazepine:May lead to symptomatic hyponatremia.\n\n " }

Ion Exchange Resins:Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins would potentially minimize the interaction [see Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "\nIon Exchange Resins:Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins would potentially minimize the interaction\n \n [see Clinical Pharmacology (12.3)].\n" }

Cyclosporine:Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.

{ "type": "p", "children": [], "text": "\nCyclosporine:Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.\n\n " }

Risk Summary

Amlodipine/valsartan/hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Published reports include cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan (see Clinical Considerations).

When pregnancy is detected, discontinue Amlodipine/valsartan/hydrochlorothiazide as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions

Valsartan

Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death.

Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in uteroexposure to Amlodipine/valsartan/hydrochlorothiazide for hypotension, oliguria, and hyperkalemia. In neonates with a history of in uteroexposure to Amlodipine/valsartan/hydrochlorothiazide, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function.

Hydrochlorothiazide

Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (preeclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of HCTZ for other indications (e.g., heart disease) in pregnancy should be avoided.

Data

Animal Data

Valsartan and Amlodipine

In rats, administered 20 mg/kg/day amlodipine plus 320 mg/kg/day valsartan, treatment-related maternal and fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were noted with the high dose combination. This corresponds to dose multiples of 9 and 19.5 times, respectively, the maximum recommended human dose (MRHD) of 10 mg/day for amlodipine and 320 mg/day for valsartan (based on body surface area and considering a 60 kg patient).

Hydrochlorothiazide

No teratogenic effects were observed when hydrochlorothiazide was administered to mice and rats via gavage at doses of up to 3,000 and 1,000 mg/kg/day (608 and 405 times the MRHD), on gestation days 6 through 15.

Risk Summary

There is limited information regarding the presence of Amlodipine/valsartan/hydrochlorothiazide in human milk, the effects on the breastfed infant, or the effects on milk production. Hydrochlorothiazide is present in human milk and valsartan is present in rat milk. Limited published studies report that amlodipine is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, advise a nursing woman that breastfeeding is not recommended during treatment with Amlodipine/valsartan/hydrochlorothiazide.

Data

Valsartan was detected in the milk of lactating rats 15 minutes after oral administration of a 3 mg/kg dose.

The safety and effectiveness of amlodipine/valsartan/hydrochlorothiazide in pediatric patients have not been established.

Amlodipine

Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60% [see Clinical Pharmacology (12.3)]. The recommended starting dose of amlodipine 2.5 mg is not an available strength with amlodipine/valsartan/hydrochlorothiazide [see Clinical Studies (14)].

Safety and effectiveness of amlodipine/valsartan/hydrochlorothiazide in patients with severe renal impairment (CrCl < 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.

Amlodipine

Exposure to amlodipine is increased in patients with hepatic insufficiency.  The recommended initial dose of amlodipine in patients with hepatic impairment is 2.5 mg, which is not an available strength with amlodipine/valsartan/hydrochlorothiazide [see Clinical Pharmacology (12.3)].

Valsartan

No dose adjustment is necessary for patients with mild-to-moderate disease. No dosing recommendations can be provided for patients with severe liver disease.

Hydrochlorothiazide

Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, institute supportive treatment.

{ "type": "p", "children": [], "text": "\nLimited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, institute supportive treatment." }

Amlodipine

{ "type": "p", "children": [], "text": "\nAmlodipine\n" }

Single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg amlodipine in mice and rats, respectively, caused deaths. Single oral doses equivalent to 4 or more mg/kg amlodipine in dogs (11 or more times the MRHD on a mg/m 2basis) caused a marked peripheral vasodilation and hypotension.

{ "type": "p", "children": [], "text": "Single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg amlodipine in mice and rats, respectively, caused deaths. Single oral doses equivalent to 4 or more mg/kg amlodipine in dogs (11 or more times the MRHD on a mg/m\n \n 2basis) caused a marked peripheral vasodilation and hypotension.\n\n " }

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension. In humans, experience with intentional overdosage of amlodipine is limited. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

{ "type": "p", "children": [], "text": "Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension. In humans, experience with intentional overdosage of amlodipine is limited. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported." }

If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, initiate cardiovascular support, including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.

{ "type": "p", "children": [], "text": "If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, initiate cardiovascular support, including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption." }

Valsartan

{ "type": "p", "children": [], "text": "\nValsartan\n" }

Depressed level of consciousness, circulatory collapse, and shock have been reported.

{ "type": "p", "children": [], "text": "Depressed level of consciousness, circulatory collapse, and shock have been reported." }

Valsartan is not removed from the plasma by hemodialysis.

{ "type": "p", "children": [], "text": "Valsartan is not removed from the plasma by hemodialysis." }

Valsartan was without grossly observable adverse effects at single oral doses up to 2,000 mg/kg in rats and up to 1,000 mg/kg in marmosets, except for salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 31 times, respectively, the MRHD on a mg/m 2basis) (Calculations assume an oral dose of 320 mg/day and a 60-kg patient).

{ "type": "p", "children": [], "text": "Valsartan was without grossly observable adverse effects at single oral doses up to 2,000 mg/kg in rats and up to 1,000 mg/kg in marmosets, except for salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 31 times, respectively, the MRHD on a mg/m\n \n 2basis) (Calculations assume an oral dose of 320 mg/day and a 60-kg patient).\n\n " }

Hydrochlorothiazide

{ "type": "p", "children": [], "text": "\nHydrochlorothiazide\n" }

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The most common signs and symptoms observed in patients are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

{ "type": "p", "children": [], "text": "The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The most common signs and symptoms observed in patients are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias." }

The oral LD 50of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, 2000 and 4000 times, respectively, the MRHD on a mg/m 2basis (Calculations assume an oral dose of 25 mg/day and a 60-kg patient).

{ "type": "p", "children": [], "text": "The oral LD\n \n 50of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, 2000 and 4000 times, respectively, the MRHD on a mg/m\n \n 2basis (Calculations assume an oral dose of 25 mg/day and a 60-kg patient).\n\n " }

Valsartan and Hydrochlorothiazide

{ "type": "p", "children": [], "text": "\nValsartan and Hydrochlorothiazide\n" }

In rats and marmosets, single oral doses of valsartan up to 1524 and 762 mg/kg in combination with hydrochlorothiazide at doses up to 476 and 238 mg/kg, respectively, were very well tolerated without any treatment-related effects. These no adverse effect doses in rats and marmosets, respectively, represent 46.5 and 23 times the MRHD of valsartan and 188 and 113 times the MRHD of hydrochlorothiazide on a mg/m 2basis (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60 kg patient).

{ "type": "p", "children": [], "text": "In rats and marmosets, single oral doses of valsartan up to 1524 and 762 mg/kg in combination with hydrochlorothiazide at doses up to 476 and 238 mg/kg, respectively, were very well tolerated without any treatment-related effects. These no adverse effect doses in rats and marmosets, respectively, represent 46.5 and 23 times the MRHD of valsartan and 188 and 113 times the MRHD of hydrochlorothiazide on a mg/m\n \n 2basis (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60 kg patient).\n\n " }

Amlodipine/valsartan/hydrochlorothiazide is a fixed combination of amlodipine, valsartan and hydrochlorothiazide.

{ "type": "p", "children": [], "text": "\nAmlodipine/valsartan/hydrochlorothiazide is a fixed combination of amlodipine, valsartan and hydrochlorothiazide." }

Amlodipine/valsartan/hydrochlorothiazide contains the besylate salt of amlodipine, a dihydropyridine calcium channel blocker (CCB). Amlodipine besylate, USP is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate's chemical name is 3-Ethyl 5-methyl (±)-2-[(2-aminoethoxy)methyl]4-( o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulfonate; its structural formula is:

{ "type": "p", "children": [], "text": "Amlodipine/valsartan/hydrochlorothiazide contains the besylate salt of amlodipine, a dihydropyridine calcium channel blocker (CCB). Amlodipine besylate, USP is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate's chemical name is 3-Ethyl 5-methyl (±)-2-[(2-aminoethoxy)methyl]4-(\n \n o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulfonate; its structural formula is:\n\n " }

Its empirical formula is C 20H 25ClN 2O 5•C 6H 6O 3S and its molecular weight is 567.1. Valsartan, USP is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is a white to practically white fine powder, soluble in ethanol and methanol and slightly soluble in water. Valsartan's chemical name is N-(1-oxopentyl)-N-[[2′-(1 H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine; its structural formula is:

{ "type": "p", "children": [], "text": "\nIts empirical formula is C\n \n 20H\n \n 25ClN\n \n 2O\n \n 5•C\n \n 6H\n \n 6O\n \n 3S and its molecular weight is 567.1. Valsartan, USP is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is a white to practically white fine powder, soluble in ethanol and methanol and slightly soluble in water. Valsartan's chemical name is N-(1-oxopentyl)-N-[[2′-(1\n \n H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine; its structural formula is:\n\n " }

Its empirical formula is C 24H 29N 5O 3and its molecular weight is 435.5.

{ "type": "p", "children": [], "text": "\nIts empirical formula is C\n \n 24H\n \n 29N\n \n 5O\n \n 3and its molecular weight is 435.5.\n\n " }

Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

{ "type": "p", "children": [], "text": "Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in\n \n n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2\n \n H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.\n\n " }

Hydrochlorothiazide is a thiazide diuretic. Its empirical formula is C 7H 8ClN 3O 4S 2, its molecular weight is 297.73, and its structural formula is:

{ "type": "p", "children": [], "text": "Hydrochlorothiazide is a thiazide diuretic. Its empirical formula is C\n \n 7H\n \n 8ClN\n \n 3O\n \n 4S\n \n 2, its molecular weight is 297.73, and its structural formula is:\n\n " }

Amlodipine/valsartan/hydrochlorothiazide film-coated tablets are formulated in five strengths for oral administration with a combination of amlodipine besylate, valsartan and hydrochlorothiazide, providing for the following available combinations: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg and 10/320/25 mg amlodipine besylate/valsartan/hydrochlo rothiazide. The inactive ingredients for all strengths of the tablets include microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate, Additionally, the 5/160/12.5 mgstrength contains polyethylene glycol, polyvinyl alcohol, titanium dioxide and talc; the 10/320/25  mgstrength contains the same ingredients as the 5/160/12.5  mgstrength; the 5/160/25  mgstrength contains lactose monohydrate, hypromellose, triacetin, D&C Yellow #10, titanium dioxide, and FD&C Yellow #6; the 10/160/12.5  mgstrength contains FD&C Yellow #6, triethyl citrate, yellow iron oxide, hypromellose and titanium dioxide, lactose monohydrate; and the 10/160/25  mgstrength contains hypromellose, titanium dioxide, D&C Yellow #10, macrogol and polysorbate.

{ "type": "p", "children": [], "text": "\nAmlodipine/valsartan/hydrochlorothiazide film-coated tablets are formulated in five strengths for oral administration with a combination of amlodipine besylate, valsartan and hydrochlorothiazide, providing for the following available combinations: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg and 10/320/25 mg amlodipine besylate/valsartan/hydrochlo rothiazide. The inactive ingredients for all strengths of the tablets include microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate, Additionally, the\n \n 5/160/12.5 mgstrength contains polyethylene glycol, polyvinyl alcohol, titanium dioxide and talc; the\n \n 10/320/25 \n \n mgstrength contains the same ingredients as the\n \n 5/160/12.5 \n \n mgstrength; the\n \n 5/160/25 \n \n mgstrength contains lactose monohydrate, hypromellose, triacetin, D&C Yellow #10, titanium dioxide, and FD&C Yellow #6; the\n \n 10/160/12.5 \n \n mgstrength contains FD&C Yellow #6, triethyl citrate, yellow iron oxide, hypromellose and titanium dioxide, lactose monohydrate; and the\n \n 10/160/25 \n \n mgstrength contains hypromellose, titanium dioxide, D&C Yellow #10, macrogol and polysorbate.\n\n " }

The active ingredients of amlodipine/valsartan/hydrochlorothiazide target 3 separate mechanisms involved in blood pressure regulation. Specifically, amlodipine blocks the contractile effects of calcium on cardiac and vascular smooth muscle cells; valsartan blocks the vasoconstriction and sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle, adrenal and renal cells; and hydrochlorothiazide directly promotes the excretion of sodium and chloride in the kidney leading to reductions in intravascular volume. A more detailed description of the mechanism of action of each individual component follows.

Amlodipine

Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitrobut such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Valsartan

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an AT 2receptor found in many tissues, but AT 2is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20000-fold) for the AT 1receptor than for the AT 2receptor. The increased plasma levels of angiotensin following AT 1receptor blockade with valsartan may stimulate the unblocked AT 2receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT 1receptor about one-200 ththat of valsartan itself.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

Amlodipine/valsartan/hydrochlorothiazide has been shown to be effective in lowering blood pressure. The 3 components of amlodipine/valsartan/hydrochlorothiazide lower the blood pressure through complementary mechanisms, each working at a separate site and blocking different effector pathways. The pharmacodynamics of each individual component is described below.

Amlodipine/valsartan/hydrochlorothiazide has not been studied in indications other than hypertension.

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic, once-daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when coadministered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of electrocardiographic (ECG) parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter ECG intervals or produce higher degrees of AV blocks.

Amlodipine has indications other than hypertension which are described in its full prescribing information.

Drug Interactions

Sildenafil

When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see Drug Interactions (7)].

Valsartan

Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available.

Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed.

Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic blood pressure, usually with little or no orthostatic change.

Valsartan has indications other than hypertension which are described in its full prescribing information.

Hydrochlorothiazide

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Amlodipine/Valsartan/Hydrochlorothiazide

Following oral administration of amlodipine/valsartan/hydrochlorothiazide in normal healthy adults, peak plasma concentrations of amlodipine, valsartan and HCTZ are reached in about 6 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and HCTZ from Amlodipine/valsartan/hydrochlorothiazide are the same as when administered as individual dosage forms.

The bioavailability of amlodipine, valsartan, and HCTZ were not altered when amlodipine/valsartan/hydrochlorothiazide was administered with food. Amlodipine/valsartan/hydrochlorothiazide may be administered with or without food.

Amlodipine

Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Valsartan

Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2 to 4 hours. Absolute bioavailability is about 25% (range 10% to 35%).

The steady state volume of distribution of valsartan after intravenous administration is 17 L indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.

Valsartan shows biexponential decay kinetics following intravenous administration with an average elimination half-life of about 6 hours. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitrometabolism studies involving recombinant CYP450 enzymes indicated that the CYP2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP450 isozymes at clinically relevant concentrations. CYP450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.

Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).

Hydrochlorothiazide

The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (C max) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.

Hydrochlorothiazide binds to albumin (40% to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline biexponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.

About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.

Specific Populations

Geriatric:Elderly patients have decreased clearance of amlodipine with a resulting increase in peak plasma levels, elimination half-life, and AUC. Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. Limited amount of data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.

Gender :Pharmacokinetics of valsartan do not differ significantly between males and females.

Race:Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency:The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Valsartan has not been studied in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis.

In a study in individuals with impaired renal function, the mean elimination half-life of hydrochlorothiazide was doubled in individuals with mild/moderate renal impairment (30 < CrCl < 90 mL/min) and tripled in severe renal impairment (CrCl ≤ 30 mL/min), compared to individuals with normal renal function (CrCl > 90 mL/min) [see Use in Specific Populations (8.6)]. 

Hepatic Insufficiency:Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60%. On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex, and weight) [see Use in Specific Populations (8.7)]. 

Drug Interactions

Amlodipine:

In vitrodata in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Impact of Other Drugs on Amlodipine

Coadministered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

CYP3A Inhibitors: Coadministration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions (7)].

Impact of Amlodipine on Other Drugs

Coadministered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Simvastatin: Coadministration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone [see Drug Interactions (7)].

Cyclosporine: A prospective study in renal transplant patients (N = 11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions (7)].

Tacrolimus: A prospective study in healthy Chinese volunteers (N = 9) with CYP3A5 expressers showed a 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N = 6). However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7)].

Valsartan

No clinically significant pharmacokinetic interactions were observed when Diovan (valsartan) was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.

Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.

Transporters:The results from an in vitrostudy with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

Hydrochlorothiazide:

Drugs That Alter Gastrointestinal Motility:The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.

Cholestyramine:In a dedicated drug interaction study, administration of cholestyramine 2 hours before hydrochlorothiazide resulted in a 70% reduction in exposure to hydrochlorothiazide. Further, administration of hydrochlorothiazide 2 hours before cholestyramine resulted in 35% reduction in exposure to hydrochlorothiazide.

Antineoplastic Agents (e.g., cyclophosphamide, methotrexate):Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Alcohol, Barbiturates, or Narcotics:Potentiation of orthostatic hypotension may occur.

Skeletal Muscle Relaxants:Possible increased responsiveness to muscle relaxants, such as curare derivatives.

Digitalis Glycosides:Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to digoxin toxicity.

Studies with Amlodipine/Valsartan/Hydrochlorothiazide: No carcinogenicity, mutagenicity or fertility studies have been conducted with this combination. However, these studies have been conducted for amlodipine, valsartan and hydrochlorothiazide alone. Based on the preclinical safety and human pharmacokinetic studies, there is no indication of any toxicologically significant adverse interaction between these components.

Studies with Amlodipine:Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m 2basis, similar to the MRHD of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m 2basis, about 2.5 times the MRHD. (Calculations based on a 60 kg patient).

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m 2basis).

Studies with Valsartan:There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at concentrations calculated to provide doses of up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.4 and 6 times, respectively, the MRHD of 320 mg/day on a mg/m 2basis (Calculations based on a 60 kg patient).

Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonellaand E. coli, a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and a rat micronucleus test.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses of up to 200 mg/kg/day. This dose is about 6 times the MRHD on a mg/m 2basis.

Studies with Hydrochlorothiazide:Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. 

Hydrochlorothiazide was not genotoxic in vitroin the Ames mutagenicity assay of Salmonella Typhimuriumstrains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivoin assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitroCHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays and in the Aspergillus Nidulans non-disjunction assay.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed via diet at doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses of hydrochlorothiazide in mice and rats are 19 and 1.5 times, respectively, the MRHD on a mg/m 2basis (Calculations assume an oral dose of 25 mg/day and a 60-kg patient).

Amlodipine/valsartan/hydrochlorothiazide was studied in a double-blind, active controlled study in hypertensive patients. A total of 2271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg) received treatments of amlodipine/valsartan/HCTZ 10/320/25 mg, valsartan/HCTZ 320/25 mg, amlodipine/ valsartan 10/320 mg, or HCTZ/amlodipine 25/10 mg. At study initiation, patients assigned to the 2-component arms received lower doses of their treatment combination while patients assigned to the amlodipine/valsartan/hydrochlorothiazide arm received 160/12.5 mg valsartan/hydrochlorothiazide. After 1 week, amlodipine/valsartan/hydrochlorothiazide patients were titrated to 5/160/12.5 mg amlodipine/valsartan/hydrochlorothiazide, while all other patients continued receiving their initial doses. After 2 weeks, all patients were titrated to their full treatment dose. A total of 55% of patients were male, 14% were 65 years or older, 72% were Caucasian, and 17% were black.

{ "type": "p", "children": [], "text": "\nAmlodipine/valsartan/hydrochlorothiazide was studied in a double-blind, active controlled study in hypertensive patients. A total of 2271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg) received treatments of amlodipine/valsartan/HCTZ 10/320/25 mg, valsartan/HCTZ 320/25 mg, amlodipine/ valsartan 10/320 mg, or HCTZ/amlodipine 25/10 mg. At study initiation, patients assigned to the 2-component arms received lower doses of their treatment combination while patients assigned to the amlodipine/valsartan/hydrochlorothiazide arm received 160/12.5 mg valsartan/hydrochlorothiazide. After 1 week, amlodipine/valsartan/hydrochlorothiazide patients were titrated to 5/160/12.5 mg amlodipine/valsartan/hydrochlorothiazide, while all other patients continued receiving their initial doses. After 2 weeks, all patients were titrated to their full treatment dose. A total of 55% of patients were male, 14% were 65 years or older, 72% were Caucasian, and 17% were black." }

At Week 8, the triple combination therapy produced greater reductions in blood pressure than each of the 3 dual combination treatments (p < 0.0001 for both diastolic and systolic blood pressures reductions). The reductions in systolic/ diastolic blood pressure with amlodipine/valsartan/hydrochlorothiazide were 7.6/5.0 mmHg greater than with valsartan/ HCTZ, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/HCTZ (see Figure 1). The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose of amlodipine/ valsartan/hydrochlorothiazide (see Figure 2 and Figure 3). As the pivotal study was an active-controlled trial, the treatment effects shown in Figures 1, 2, and 3 include a placebo effect of unknown size.

{ "type": "p", "children": [], "text": "At Week 8, the triple combination therapy produced greater reductions in blood pressure than each of the 3 dual combination treatments (p < 0.0001 for both diastolic and systolic blood pressures reductions). The reductions in systolic/ diastolic blood pressure with amlodipine/valsartan/hydrochlorothiazide were 7.6/5.0 mmHg greater than with valsartan/ HCTZ, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/HCTZ (see Figure 1). The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose of amlodipine/ valsartan/hydrochlorothiazide (see Figure 2 and Figure 3). As the pivotal study was an active-controlled trial, the treatment effects shown in Figures 1, 2, and 3 include a placebo effect of unknown size." }

A subgroup of 283 patients was studied with ambulatory blood pressure monitoring. The blood pressure lowering effect in the triple therapy group was maintained throughout the 24-hour period (see Figure 4 and Figure 5).

{ "type": "p", "children": [], "text": "\nA subgroup of 283 patients was studied with ambulatory blood pressure monitoring. The blood pressure lowering effect in the triple therapy group was maintained throughout the 24-hour period (see Figure 4 and Figure 5)." }

There are no trials of the amlodipine/valsartan/hydrochlorothiazide combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but both the amlodipine and hydrochlorothiazide components and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits.

{ "type": "p", "children": [], "text": "\nThere are no trials of the amlodipine/valsartan/hydrochlorothiazide combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but both the amlodipine and hydrochlorothiazide components and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits." }

Amlodipine/valsartan/hydrochlorothiazide is available as film-coated tablets containing amlodipine besylate equivalent to 5 mg or 10 mg of amlodipine free-base with valsartan 160 mg or 320 mg and hydrochlorothiazide 12.5 mg or 25 mg providing for the following available combinations: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg or 10/320/25 mg. All strengths are packaged in bottles of 30, 90 and 500 tablets.

{ "type": "p", "children": [], "text": "Amlodipine/valsartan/hydrochlorothiazide is available as film-coated tablets containing amlodipine besylate equivalent to 5 mg or 10 mg of amlodipine free-base with valsartan 160 mg or 320 mg and hydrochlorothiazide 12.5 mg or 25 mg providing for the following available combinations: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg or 10/320/25 mg. All strengths are packaged in bottles of 30, 90 and 500 tablets." }

5 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets -White to off-white, film coated, oval shaped biconvex tablets, debossed with "P" on one side of the tablet and "172" on the other

{ "type": "p", "children": [], "text": "\n5 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets -White to off-white, film coated, oval shaped biconvex tablets, debossed with \"P\" on one side of the tablet and \"172\" on the other\n " }

Bottles of 30 NDC 51407-668-30

{ "type": "p", "children": [], "text": " Bottles of 30 NDC 51407-668-30" }

10 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets– Peach to light brown, film coated, oval shaped biconvex tablets, debossed with "P" on one side of the tablet and "174" on the other.

{ "type": "p", "children": [], "text": "\n10 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets– Peach to light brown, film coated, oval shaped biconvex tablets, debossed with \"P\" on one side of the tablet and \"174\" on the other.\n " }

Bottles of 30 NDC 51407-670-30

{ "type": "p", "children": [], "text": " Bottles of 30 NDC 51407-670-30" }

5 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets –Yellow, film-coated, oval shaped biconvex tablets debossed with "P" on one side of the tablet and "173" on the other.

{ "type": "p", "children": [], "text": "\n5 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets –Yellow, film-coated, oval shaped biconvex tablets debossed with \"P\" on one side of the tablet and \"173\" on the other.\n " }

Bottles of 30 NDC 51407-669-30

{ "type": "p", "children": [], "text": " Bottles of 30 NDC 51407-669-30" }

10 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets –Bright yellow, film-coated oval shaped, biconvex tablets debossed with "P" on one side of the tablet and "185" on the other.

{ "type": "p", "children": [], "text": "\n10 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets –Bright yellow, film-coated oval shaped, biconvex tablets debossed with \"P\" on one side of the tablet and \"185\" on the other.\n " }

Bottles of 30 NDC 51407-671-30

{ "type": "p", "children": [], "text": " Bottles of 30 NDC 51407-671-30" }

10 mg amlodipine /320 mg valsartan /25 mg hydrochlorothiazide Tablets– White to off-white, film coated, oval shaped biconvex tablets, debossed with "P" on one side of the tablet and "175" on the other

{ "type": "p", "children": [], "text": "\n10 mg amlodipine /320 mg valsartan /25 mg hydrochlorothiazide Tablets– White to off-white, film coated, oval shaped biconvex tablets, debossed with \"P\" on one side of the tablet and \"175\" on the other\n " }

Bottles of 30 NDC 51407-672-30

{ "type": "p", "children": [], "text": " Bottles of 30 NDC 51407-672-30" }

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15º to 30°C (59º to 86°F)

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F); excursions permitted to 15º to 30°C (59º to 86°F)" }

[see USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "[see USP Controlled Room Temperature.]" }

Protect from moisture.

{ "type": "p", "children": [], "text": "Protect from moisture." }

Dispense in tight container (USP).

{ "type": "p", "children": [], "text": "Dispense in tight container (USP)." }

<div class="scrollingtable"><table class="Noautorules" width="831"> <colgroup> <col width="831"/> </colgroup> <tbody class="Headless"> <tr> <td align="center" valign="top"><span class="Bold">Patient Information</span> <br/> <span class="Bold">Amlodipine/Valsartan/Hydrochlorothiazide</span> <br/> <span class="Bold">(am-LOE-di-peen, val-SAR-tan, HYE-droe-klor-oh THYE-a-zide) Tablets</span></td> </tr> <tr> <td align="left" valign="top">Read the Patient Information that comes with amlodipine/valsartan/hydrochlorothiazide before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. <br/> <br/> <span class="Bold">What is the most important information I should know about Amlodipine/ Valsartan/Hydrochlorothiazide?</span> <ul class="Disc"> <li>Amlodipine/valsartan/hydrochlorothiazide can cause harm or death to an unborn baby.</li> <li>Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.</li> <li>If you get pregnant while taking amlodipine/valsartan/hydrochlorothiazide, tell your doctor right away.</li> </ul> <br/> <span class="Bold">What is Amlodipine/Valsartan/Hydrochlorothiazide?</span> <br/> Amlodipine/valsartan/hydrochlorothiazide contains 3 prescription medicines: <ol class="Arabic"> <li>amlodipine, a calcium channel blocker</li> <li>valsartan, an angiotensin receptor blocker, and</li> <li>hydrochlorothiazide, a diuretic (water pill)</li> </ol> Amlodipine/valsartan/hydrochlorothiazide may be used to lower blood pressure in adults when 2 medicines to lower your high blood pressure are not enough. <br/> Amlodipine/valsartan/hydrochlorothiazide has not been studied in children under 18 years of age. <br/> <br/> <span class="Bold">Who should not take Amlodipine/Valsartan/Hydrochlorothiazide?</span> <br/> <span class="Bold">Do not take Amlodipine/Valsartan/Hydrochlorothiazide if you have low or no urine output (anuria).</span> <br/> <br/> <span class="Bold">What should I tell my doctor before taking Amlodipine/Valsartan/Hydrochlorothiazide?</span> <br/> Tell your doctor about all of your medical conditions, including if you: <ul class="Disc"> <li> <span class="Bold">are pregnant or plan to become pregnant</span>. See <span class="Bold">"What is the most important information I should know about amlodipine/valsartan/hydrochlorothiazide?"</span> </li> <li> <span class="Bold">are breastfeeding or plan to breastfeed</span>. Amlodipine/valsartan/hydrochlorothiazide is present in human milk. It is not known whether amlodipine/valsartan/ hydrochlorothiazide affects your breastfed baby or milk production. Do not breastfeed while you are taking amlodipine/valsartan/hydrochlorothiazide. </li> <li>are allergic to any of the ingredients in amlodipine/valsartan/hydrochlorothiazide. See the end of this leaflet for a list of the ingredients in amlodipine/ valsartan/hydrochlorothiazide.</li> <li>have heart problems</li> <li>have liver problems</li> <li>have kidney problems</li> <li>are vomiting or having a lot of diarrhea</li> <li>have or had gallstones</li> <li>have Lupus</li> <li>have low levels of potassium (with or without symptoms such as muscle weakness, muscle spasms, abnormal heart rhythm) or magnesium in your blood</li> <li>have high levels of calcium in your blood (with or without symptoms such as nausea, vomiting, constipation, stomach pain, frequent urination, thirst, muscle weakness, and twitching).</li> <li>have high levels of uric acid in the blood.</li> <li>have ever had a reaction called angioedema, to another blood pressure medicine. Angioedema causes swelling of the face, lips, tongue, and may cause difficulty breathing.</li> </ul> Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some of your other medicines and amlodipine/valsartan/hydrochlorothiazide could affect each other, causing serious side effects. <br/> Especially tell your doctor if you take: <br/> ● simvastatin or other cholesterol-lowering medicine <br/> ● other medicines for high blood pressure or a heart problem <br/> ● water pills ("diuretics") <br/> ● potassium supplements. Your doctor may check the amount of potassium in your blood periodically. <br/> ● salt substitute containing potassium. Your doctor may check the amount of potassium in your blood periodically. <br/> ● diabetes medicine, including insulin <br/> ● narcotic pain medicines <br/> ● sleeping pills and antiseizure medicines called barbiturates <br/> ● lithium, a medicine used to treat some types of depression <br/> ● aspirin or other medicines called nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen or naproxen <br/> ● steroids <br/> ● alcohol <br/> ● digoxin or other digitalis glycosides (a heart medicine) <br/> ● muscle relaxants (medicines used during operations) <br/> ● certain cancer medicines, like cyclophosphamide or methotrexate <br/> ● medicines used to prevent and treat fungal infections (such as ketoconazole, itraconazole). <br/> ● medicines used to treat bacterial infections (such as clarithromycin, telithromycin) <br/> ● certain antibiotics (rifamycin group), a drug used to protect against transplant rejection (cyclosporine) or an antiretroviral drug used to treat HIV/AIDS infection (ritonavir). These drugs may increase the effect of valsartan. <br/> Know the medicines you take. Keep a list of your medicines and show it to your doctor or pharmacist when you get a new medicine. <br/> <span class="Bold">How should I take Amlodipine/Valsartan/Hydrochlorothiazide?</span> <ul class="Disc"> <li>Take amlodipine/valsartan/hydrochlorothiazide exactly as your doctor tells you.</li> <li>Take amlodipine/valsartan/hydrochlorothiazide one time each day.</li> <li>Amlodipine/valsartan/hydrochlorothiazide can be taken with or without food.</li> <li>If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Just take the next dose at the regular time.</li> <li>If you take too much amlodipine/valsartan/hydrochlorothiazide, call your doctor or Poison Control Center, or go to the emergency room.</li> <li>Tell all your doctors and dentist you are taking amlodipine/valsartan/hydrochlorothiazide. This is especially important if you:</li> </ul> ○ are going to have surgery <br/> ○ go for kidney dialysis <br/> <span class="Bold">What are the possible side effects of Amlodipine/Valsartan/Hydrochlorothiazide?</span> <br/> Amlodipine/valsartan/hydrochlorothiazide may cause <span class="Bold">serious side effects</span>including: <ul class="Disc"> <li> <span class="Bold">harm to an unborn baby causing injury or death.</span>See <span class="Bold">"What is the most important information I should know about Amlodipine/Valsartan/Hydrochlorothiazide?"</span> </li> <li> <span class="Bold">low blood pressure</span>(hypotension). Low blood pressure is most likely to happen if you: </li> </ul> ○ take water pills <br/> ○ are on a low-salt diet <br/> ○ have heart problems <br/> ○ get dialysis treatments <br/> ○ get sick with vomiting or diarrhea <br/> ○ drink alcohol <br/> Lie down if you feel faint or dizzy. If you faint (lose consciousness), stop taking amlodipine/valsartan/hydrochlorothiazide. Call your doctor right away. <ul class="Disc"> <li>Get emergency help if you get worse chest pain or chest pain that does not go away.</li> <li> <span class="Bold">kidney problems.</span>Kidney problems may become worse in people that already have kidney disease. Some people will have changes in blood tests for kidney function and may need a lower dose of amlodipine/valsartan/hydrochlorothiazide. Call your doctor if you have swelling in your feet, ankles, or hands, or unexplained weight gain. If you have heart failure, your doctor should check your kidney function before prescribing amlodipine/valsartan/hydrochlorothiazide. </li> <li> <span class="Bold">laboratory blood test changes in people with heart failure.</span>Some people with heart failure who take valsartan, one of the medicines in amlodipine/valsartan/hydrochlorothiazide, have changes in blood tests including increased potassium and decreased kidney function. </li> <li> <span class="Bold">allergic reactions</span> </li> <li> <span class="Bold">skin rash.</span>Call your doctor right away if you get an unusual skin rash. </li> <li> <span class="Bold">eye problems.</span>One of the medicines in amlodipine/valsartan/hydrochlorothiazide can cause eye problems that may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of starting amlodipine/valsartan/ hydrochlorothiazide. Tell your doctor right away if you have: </li> </ul> o decrease in vision <br/> o eye pain <br/> The <span class="Bold">most common</span>side effects of amlodipine/valsartan/hydrochlorothiazide include: <ul class="Disc"> <li>dizziness</li> <li>swelling (edema) of the hands, ankles, or feet</li> <li>headache</li> <li>indigestion</li> <li>tiredness</li> <li>muscle spasms</li> <li>back pain</li> <li>nausea</li> </ul> Protect your skin from the sun and undergo regular skin cancer screening, as one of the medicines in amlodipine/valsartan/hydrochlorothiazide may cause non-melanoma skin cancer. <br/> Tell your doctor if you have any side effect that bothers you or that does not go away. <br/> These are not all the possible side effects of amlodipine/valsartan/hydrochlorothiazide. For more information, ask your doctor or pharmacist. <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <br/> <span class="Bold">How should I store Amlodipine/Valsartan/Hydrochlorothiazide?</span> <ul class="Disc"> <li>Store amlodipine/valsartan/hydrochlorothiazide at 68° to 77°F (20° to 25°C).</li> <li>Keep amlodipine/valsartan/hydrochlorothiazide dry (protect it from moisture).</li> </ul> <p class="First"> <span class="Bold">Keep Amlodipine/Valsartan/Hydrochlorothiazide and all medicines out of the reach of children.</span> <br/> <span class="Bold">General Information about Amlodipine/Valsartan/Hydrochlorothiazide</span> <br/> Medicines are sometimes prescribed for conditions that are not mentioned in the patient information leaflet. Do not use amlodipine/valsartan/hydrochlorothiazide for a condition for which it was not prescribed. Do not give amlodipine/valsartan/ hydrochlorothiazide to other people, even if they have the same symptoms that you have. It may harm them. <br/> This patient information leaflet summarizes the most important information about amlodipine/valsartan/hydrochlorothiazide. If you would like more information about amlodipine/valsartan/hydrochlorothiazide, talk with your doctor. You can ask your doctor or pharmacist for information about amlodipine/valsartan/hydrochlorothiazide that is written for health professionals. For more information go to www.strides.com or call 1-877-244-9825 <span class="Bold">.</span> <br/> <span class="Bold">What are the ingredients in Amlodipine/Valsartan/Hydrochlorothiazide?</span> <br/> Active ingredients: amlodipine besylate, valsartan and hydrochlorothiazide <br/> The inactive ingredients for all strengths of the tablets include microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate, Additionally, the <span class="Bold">5/160/12.5 mg</span>strength contains polyethylene glycol, polyvinyl alcohol, titanium dioxide and talc; the <span class="Bold">10/320/25</span><span class="Bold">mg</span>strength contains the same ingredients as the <span class="Bold">5/160/12.5</span><span class="Bold">mg</span>strength; the <span class="Bold">5/160/25</span><span class="Bold">mg</span>strength contains lactose monohydrate, hypromellose, triacetin, D&amp;C Yellow #10, titanium dioxide, and FD&amp;C Yellow #6; the <span class="Bold">10/160/12.5</span><span class="Bold">mg</span>strength contains FD&amp;C Yellow #6, triethyl citrate, yellow iron oxide, hypromellose and titanium dioxide, lactose monohydrate; and the <span class="Bold">10/160/25</span><span class="Bold">mg</span>strength contains hypromellose, titanium dioxide, D&amp;C Yellow #10, macrogol and polysorbate. <br/> <span class="Bold">What is high blood pressure (hypertension)?</span> <br/> Blood pressure is the force of blood in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. Amlodipine/valsartan/hydrochlorothiazide can help your blood vessels relax so your blood pressure is lower. Medicines that lower blood pressure lower your chance of having a stroke or heart attack. <br/> High blood pressure makes the heart work harder to pump blood throughout the body and causes damage to blood vessels. If high blood pressure is not treated, it can lead to stroke, heart attack, heart failure, kidney failure and vision problems. <br/> Distributed by: <br/> <span class="Bold">Strides Pharma Inc.</span> <br/> East Brunswick, NJ 08816 <br/> Revised: 04/2025 <br/> OS172-01-1-07 </p> <p></p> <p>Marketed by:</p> <p>GSMS, Inc.</p> <p>Camarillo, CA 93012 USA</p> </td> </tr> </tbody> </table></div>